Office of Management and Budget (OMB) and Office of Science and Technology Policy (OSTP)

Comments on the Interagency Science Consultation Draft IRIS Assessment of RDX (dated September 

2014)

Date: October 31, 2014

October 28, 2014

Interagency Review (Step 3) of EPA IRIS Toxicological Review of RDX

Dear EPA IRIS:

Thank you for the opportunity to provide comments on the draft Toxicological Review of Hexahydro1,3,5-trinitro-1,3,5-triazine (RDX). We have comments on both the Preamble and the dose-response 

assessment. 

Preamble Comments

There are statements in the Preamble that amount to policy positions or decisions rather than scientific 

ones. Several of these are noted here. The focus of the Preamble should be to describe the IRIS process 

as a scientific one.

• p. xv, lines 40-49: “Step 5. Revision of draft Toxicological 40 Review and development of 

draft IRIS 41 summary. The draft assessment is 42 revised to reflect the peer review 43 

comments, public comments, and newly 44 published studies that are critical to the 45 

conclusions of the assessment. The 46 disposition of peer review comments and 47 public 

comments becomes part of the 48 public record.” 

o Comment: Should there be text to explain that if necessary, the document may 

undergo a focused 2nd round peer review by the peer review panel? Is there a 

policy yet?

• p. xv, line 53. Need period after the bold header sentence that begins with “Step 6.”

• p. xvi, lines 59-60: “...some population-based surveys (for example, NHANES) provide the 

strongest epidemiological information...” 

o Comment: Population-based surveys, aka cross-sectional studies, should not be 

considered in the same category of clinical studies (which EPA has not mentioned), 

cohort studies, and case-control studies. Surveys have inherent methodological 

weaknesses that are well documented in epidemiological methodology texts, often 

to the extent that they are primarily considered hypothesis generating. The 

recommended remedy here is to split the first sentence, then add special reference 

to NHANES as a quality example of a survey design. “Cohort and case-control studies 

provide the strongest epidemiological evidence, especially if they collect 

information about individual exposures and effects. Population-based surveys, if 

conducted rigorously such as the NHANES survey, can also provide supportive 

information.”
• p. xvi, lines 65-72: “Ecological studies (geographic 65 correlation studies) relate exposures 

66 and effects by geographic area. They 67 can provide strong evidence if there 68 are large 

exposure contrasts between 69 geographic areas, relatively little 70 exposure variation 

within study areas, 71 and population migration is limited. “

o Comment: Aren't these types of studies typically considered to be the weakest 

study designs for establishing chemical/hazard relationships (i.e. associations or 

causality)? These are hypothesis generating studies, and not of the rigor for 

demonstrating causality. Deleting the term “strong” would be a minimal necessary 

change to reflect this well-acknowledged limitation of ecological designs. 

• p. xvi, lines 73-79: “Case reports of high or accidental 73 exposure lack definition of the 74 

population at risk and the expected 75 number of cases. They can provide 76 information 

about a rare effect or 77 about the relevance of analogous 78 results in animals.”

o Comment: There should be a caveat that case reports are (again) hypothesis 

generating types of studies (for potential hazard ID), and are inadequate for 

establishing causality.

• p. xvii, lines 34-39: “For developmental toxicity and 34 reproductive toxicity, irreversible 

effects may 35 result from a brief exposure during a critical 36 period of development. 

Accordingly, 37 specialized study designs are used for these 38 effects (U.S. EPA, 2006b, 

1998, 1996, 1991).”

o Comment: How will EPA treat the expansive literature exploring developmental tox 

endpoints that do not use the "specialized study designs" and instead are more 

"hypothesis generating" studies or academic laboratory studies? Many of these 

studies have been frequently cited in past tox reviews, but do not use the GLP study 

designs for regulatory purposes.

• p. xviii, lines 50-61: “In some situations, examination of historical 50 control data from the 

same laboratory within 51 a few years of the study may improve the 52 analysis. For an 

uncommon effect that is not 53 statistically significant compared with 54 concurrent 

controls, historical controls may 55 show that the effect is unlikely to be due to 56 chance. 

For a response that appears 57 significant against a concurrent control 58 response that is 

unusual, historical controls 59 may offer a different interpretation (U.S. EPA, 60 2005a, 

§2.2.2.1.3).”

o Comment: Is there any guidance on using historical control data in the manner 

suggested in this paragraph? Historical control data are typically used to measure 

"genetic drift" of the species being used in the laboratory, to ensure that laboratory 

practices are faithfully maintained according to adopted GLP or other guidances. 

Only concurrent control data provide an appropriate comparison to the treatment 

groups. This proposed practice – implied here as an agreed EPA policy -- would 

benefit from a more robust scientific discussion. Alternatively, deleting this section 

would have no detrimental effect on the preamble, and leave the issue to a case-bycase evaluation, which is where evaluation of historical controls ought be vis a vis 

individual study results.

• p. xviii, lines 70-75: “Effects that occur at doses associated 70 with mild maternal toxicity are 

not assumed to 71 result only from maternal toxicity. Moreover, 72 maternal effects may be 
reversible, while 73 effects on the offspring may be permanent 74 (U.S. EPA, 1998, 

§3.1.2.4.5.4; 1991, §3.1.1.4),.”

o Comment: misplaced comma at the end of the sentence. There should also be a 

caveat explaining that exposures that result in frank maternal toxicity may not be 

relevant in producing the developmental toxicity of interest, i.e., the flip side of this 

statement.

• p. xix, lines 43-49: “The finding of a large relative risk with narrow confidence intervals 

strongly suggests that an association is not due to chance, bias, or other factors.”

o Comment: Consider deleting “bias” from this sentence. Bias may indeed be the 

cause of a large relative risk, just the wrong linkage. 

• p.xx, lines 47-71: Causation standard descriptors relating epidemiological information to 

causation.

o Comment: Causation analysis inherently requires the package of considerations, 

from epidemiology, to bioassays, to mode of action, to ... the Hill criteria. Yet, here, 

EPA is imputing causation analysis based on only the epidemiological parameter. 

Has EPA used these “epidemiological causation” descriptors before? One way to 

remedy would be to simply delete the words “consistent with causation” and leave 

the “association” terminology intact, because that is what is generally being 

addressed in such summaries of the epidemiological information. 

• p. xxi, lines 33-36: “Negative results carry less weight, 33 partly because they cannot exclude 

the 34 possibility of effects in other tissues 35 (IARC, 2006).”

o Comment: Why should negative results carry less weight? I think that the genetic 

toxicology assessment should evaluate the results as a whole, and not pre-judge the 

validity of negative genetic toxicity studies. Indeed, to be balanced, EPA might also 

note publication bias against negative studies.

o p. xxi, line 60: “Toxicodynamic processes that lead to a health effect at this or

another site (also known as mode of action).Comment: Does mode of action not 

include any consideration of toxicokinetics, which this section implies? What about 

metabolism leading to toxic moieties, is this not part of the mode of action? Or 

(de)activation through stomach acids?

• p.xxi, line 73: Suggest adding “Although important, information on mode of action is not 

required for a conclusion that the agent is causally related to an effect, in circumstances 

where there is compelling information supporting such a conclusion.”

• p. xxii, lines 37-40: “It should be noted that in clinical reviews, the 37 credibility of a series of 

studies is reduced if 38 evidence is limited to studies funded by one 39 interested sector 

(Guyatt et al., 2008a).”

o Comment: This is a questionable statement. Evaluations should be based on rigor of 

study design, reproducibility, etc. not funding source. One could cite HHS (NIH or 

NTP) or EPA as interested sector funding sources.

• p.xxv, lines 3-5: “For chronic effects, daily exposures are averaged over the lifespan.”
o Comment: This is puzzling. Wouldn’t it be more accurate to say that “For chronic 

effects, daily exposures are averaged over the duration of the study, and assumed 

to continue over a lifespan in the modeling.”

• p. xxvi, lines 52-55: “Nonlinear 52 approaches generally should not be used 53 in cases 

where mode of action has not 54 ascertained.”

o Comment: Missing “been” between “has not” and “ascertained.”

Primary Comments

• p. ES-1, line 8: “Although 6 mechanistic data are insufficient to establish a mode of action (MOA) 

for RDX-induced convulsions, 7 the available information suggests that nervous system effects 

are mediated by RDX binding to the 8 picrotoxin convulsant site of the GABAA channel, resulting 

in disinhibition that leads to the onset of 9 seizures.” 

o Comment: this statement seems contradictory. The data (discussed later in the 

document) seems more than suggestive in regards to a MOA. Why is the conclusion 

“insufficient” to establish a MOA?

• p.ES-2, line 10: Table ES-1 presents the conclusory snapshot of candidate and final RfDs, but 

omits critical information on the PODs and UFs. For full transparency, extra columns should be 

added to provide this transparency. We realize that this on the next page for the chosen study 

and endpoint, but now we have a reversal of information ordering from previous IRIS summaries 

where the critical information was packaged in the first table. An additional general request – 

given this new format -- is that now there is only summary information up front, and copious 

tabulated detail on each of the studies in the supplement. EOP has asked previously, to no avail, 

for critical data from just the selected study and endpoint of interest to be included up front, 

along with the BMD Software graph of the modeling (I could not find any such BMD software 

graphs in the documents reviewed – are they in an appendix?). Otherwise, the RfD, RfC, and 

CSF numbers retain their “magic” quality, isolated by an inability to expeditiously determine

which of the many supplementary data tables is actually the origin of these reference doses. An 

alternative might be to add a link or table/page reference number with each study citation on 

this page, making the search a little easier.

• p. ES-2, line 20: “A 1% 20 response level was chosen because of the severity of the endpoint; 

this is supported by the 21 observation in Crouse et al. (2006) that for all the dose groups where 

unscheduled deaths were 22 recorded, mortality was strongly associated with convulsions.” 

Also addressed on p. ES-5 line 9, and later in the dose-response assessment.

o Comment: The rationale for a BMR of 1% needs to be better supported, especially since 

the preamble material (xxvi, lines 1-2) indicates that 5% would be the appropriate level 

for more severe effects. How is the “severity” of the endpoint determined? A 

sensitivity analysis using other BMRs (including the usual 10% BMR) is presented in the 

Supplemental Information appendix, however, it would be useful to include in the main 

document a table that compares the PODs of the selected BMR (1%) and the more usual 

10% BMR. Is there a BMD Software graph of this BMR calculation, to aid in visually 

determining the extent of the extrapolation and the variability of the empirical data? 

• p. ES-3, line 2: “...deficiencies in the toxicity database (3).” 
o Comment: This database UF was not used in the previous RDX RfD derivation. There are 

developmental and reproductive tox studies. EPA justifies the value of 3 for this UF, 

citing the lack of developmental neurobehavioral studies. Is this standard practice for 

EPA to consider this an inadequate database, and require a specific developmental 

neurobehavioral study for a neurological endpoint, and developmental studies for other 

noncancer endpoints? 

• p. 1-41, line 33: “In addition, the incidence of hepatocellular carcinomas showed a cant 33 

positive trend with dose in male, but not female, F344 rats exposed to RDX in the diet for 2 

years 34 (Levine et al., 1983) (Cochran-Armitage trend test performed for this review, p = 

0.032).” 

o Comment: struck out a misplaced word.

• p. 1-42, lines 5-12: “In the female B6C3F1 mouse study by Lish et al. (1984), the finding of a 

statistically 5 significant increase in hepatocellular tumors may have been influenced by the 

incidence of 6 hepatocellular adenomas/carcinomas in the concurrent female control mice, 

which the study 7 authors noted was relatively low (1/65). However, as noted by the authors, 

the incidence of 8 hepatocellular adenomas or carcinomas at RDX doses ≥35 mg/kg-day (19% at 

both doses) was also 9 statistically significantly elevated when compared to the mean historical 

control incidence for 10 female B6C3F1 mice in National Toxicology Program (NTP) studies 

(147/1781 or 8%; range: 11 0−20%) (Haseman et al., 1985).5

” 

o Comment: The purpose of this discussion is unclear. What is meant by "the finding of 

statistically significant increase in hepatocellular tumors may have been influenced..."?

Comments on the Peer Review Charge Questions

• There should be an explicit charge question on the use of a 1% BMR instead of the usual 10% 

BMR, and the recommended 5% BMR for more severe effects. The SAB CAAC should be 

provided with a table summarizing the sensitivity analysis of BMRs.

• There should be an explicit charge question on the database uncertainty factor.

• The Preamble should be critically reviewed by the SAB CAAC, particularly on those items that we 

commented on.